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      Identification and functional characterization of CD8 + T regulatory cells in type 1 diabetes patients

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          Abstract

          Type 1 diabetes is an autoimmune disease where autoreactive T lymphocytes destroy pancreatic beta cells. We previously reported a defect in CD4 + Tregs cell proliferation and reduced CD4 + Tregs PD-1 expression in patients. Another ‘memory-like’ regulatory subset, CD8 + Tregs, evaluated as CD8 +CD25 +FOXP3 +, has recently raised interest for their effective suppressive activity. Different CD8 + T cell populations, their proliferation capacity and expression of PD-1 molecule were evaluated by flow-cytometer analysis in newly diagnosed, long-term Type 1 diabetes patients compared to healthy normal donors. Under basal conditions, CD8 + Tregs and CD8 + Teffs were seemingly represented among study groups while there was evidence of diminished expression of PD-1 in Teff subsets of long-term patients. After 3 days of PMA/ionomycin stimulation, patients CD8 + Tregs showed decreased percentage in respect to control group. CD8 + Teffs were instead increased in long-term diabetics versus controls. PD-1 +CD8 + Tregs were represented at a much lower percentage in long-term diabetic patients, in respect to controls. Importantly, patients CD8 + Tregs and CD8 + Teffs presented a significant proliferation defect in respect to the control group. In conclusion, our study indicates that a defect of CD8 + Tregs is observed in diabetics. This subset could thus represent a novel target of immunotherapy in patients.

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          Most cited references43

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          The Programmed Death-1 (PD-1) Pathway Regulates Autoimmune Diabetes in Nonobese Diabetic (NOD) Mice

          Programmed death-1 (PD-1) receptor, an inhibitory costimulatory molecule found on activated T cells, has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance. We investigated the role of this pathway in the development of autoimmune diabetes. PD-1 or PD-L1 but not PD-L2 blockade rapidly precipitated diabetes in prediabetic female nonobese diabetic (NOD) mice regardless of age (from 1 to 10-wk-old), although it was most pronounced in the older mice. By contrast, cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) blockade induced disease only in neonates. Male NOD mice also developed diabetes after PD-1–PD-L1 pathway blockade, but NOR mice, congenic to NOD but resistant to the development of diabetes, did not. Insulitis scores were significantly higher and frequency of interferon γ–producing GAD-reactive splenocytes was increased after PD-1–PD-L1 pathway blockade compared with controls. Interestingly, PD-L1 but not PD-L2 was found to be expressed on inflamed islets of NOD mice. These data demonstrate a central role for PD-1–PD-L1 interaction in the regulation of induction and progression of autoimmune diabetes in the NOD mouse and provide the rationale to develop new therapies to target this costimulatory pathway in this disease.
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            Establishment of NOD-Pdcd1-/- mice as an efficient animal model of type I diabetes.

            Mice deficient in programmed cell death 1 (PD-1, Pdcd1), an immunoinhibitory receptor belonging to the CD28/cytotoxic T lymphocyte-associated antigen-4 family, spontaneously develop lupus-like autoimmune disease and autoimmune dilated cardiomyopathy on C57BL/6 and BALB/c backgrounds, respectively. However, how PD-1 deficiency induces different forms of autoimmune diseases on these two strains was unknown. Here, we report that PD-1 deficiency specifically accelerates the onset and frequency of type I diabetes in NOD (nonobese diabetic) mice, with strong T helper 1 polarization of T cells infiltrating into islets. These results suggest that PD-1 deficiency accelerates autoimmune predisposition of the background strain, leading to the induction of different forms of autoimmune diseases depending on the genetic background of the strain. Using NOD-Pdcd1-/- mice as an efficient animal model of type I diabetes, we screened diabetes-susceptible loci by genetic linkage analysis. The diabetic incidence of NOD-Pdcd1-/- mice was controlled by five genetic loci, including three known recessive loci [Idd (insulin-dependent diabetes) 1, Idd17, and Idd20] and two previously unidentified dominant loci [Iddp (Idd under PD-1 deficiency) 1 and Iddp2].
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              IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells

              Regulatory T cells (T reg cells) play a major role in controlling the pathogenic autoimmune process in type 1 diabetes (T1D). Interleukin 2 (IL-2), a cytokine which promotes T reg cell survival and function, may thus have therapeutic efficacy in T1D. We show that 5 d of low-dose IL-2 administration starting at the time of T1D onset can reverse established disease in NOD (nonobese diabetic) mice, with long-lasting effects. Low-dose IL-2 increases the number of T reg cells in the pancreas and induces expression of T reg cell–associated proteins including Foxp3, CD25, CTLA-4, ICOS (inducible T cell costimulator), and GITR (glucocorticoid-induced TNF receptor) in these cells. Treatment also suppresses interferon γ production by pancreas-infiltrating T cells. Transcriptome analyses show that low-dose IL-2 exerts much greater influence on gene expression of T reg cells than effector T cells (T eff cells), suggesting that nonspecific activation of pathogenic T eff cells is less likely. We provide the first preclinical data showing that low-dose IL-2 can reverse established T1D, suggesting that this treatment merits evaluation in patients with T1D.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: ValidationRole: VisualizationRole: Writing – original draft
                Role: Resources
                Role: Validation
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: Writing – original draft
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                16 January 2019
                2019
                : 14
                : 1
                : e0210839
                Affiliations
                [1 ] Infectivology and Clinical Trials Research Division, Bambino Gesù Children's Hospital, Rome, Italy
                [2 ] Endocrinology Department, Bambino Gesù Children's Hospital, Rome, Italy
                [3 ] Bambino Gesù Children's Hospital, Research Laboratories, Rome, Italy
                Mississippi State University, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-9002-3622
                http://orcid.org/0000-0003-3078-9754
                Article
                PONE-D-18-31176
                10.1371/journal.pone.0210839
                6334945
                30650147
                9591f275-c6e8-426a-8c4f-802f5372ad96
                © 2019 Pellegrino et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 29 October 2018
                : 2 January 2019
                Page count
                Figures: 7, Tables: 2, Pages: 20
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100003196, Ministero della Salute;
                Award ID: Ricerca corrente RC201702P003967
                Award Recipient :
                This work was supported by Italian Ministry of Health Ricerca corrente RC201702P003967 (AF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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